September 23, 2013

CURE Conversations: Detlev Boison, PhD

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Detlev Boison, PhD

Ph.D. Biochemistry, University of Cologne, Germany

Interim Dow Chair of Neurology & Director of Neurobiology Research
Director of Basic and Translational Research

Can you share some details about what you do?
My lab is interested in homeostatic mechanisms that define brain function and to translate those findings into novel treatment options for persons with epilepsy and related neurological conditions. I see epilepsy as a complex syndrome that is not only defined by seizures but also by associated comorbidities that may affect cognition, mood, or sleep. This more holistic view of epilepsy can best be explained by the failure of self-regulating mechanisms that affect the brain on many different levels.

One of the key regulators of homeostatic functions in the brain is the molecule adenosine, which is tightly linked to cellular energy homeostasis. In general, under conditions in which energy demands exceed supplies (e.g. during an epileptic seizure) adenosine levels rise and block all processes that consume energy, such as a seizure. Therefore, adenosine is the brain’s own seizure terminator. We found that adenosine homeostasis is compromised in the epileptic brain and that adenosine deficiency is a pathological hallmark of seizure-triggering brain areas. We developed transgenic animals with reduced adenosine in the brain; interestingly, these animals not only have seizures but also characteristic comorbid symptoms commonly found in epilepsy, such as cognitive impairment, or sleep alterations. We therefore develop therapies that reconstruct adenosine homeostasis in the brain and have shown that adenosine releasing brain implants, or stem cell grafts and gene therapy, designed to increase adenosine locally within the brain, are highly efficacious in stopping epileptic seizures in a wide range of epilepsy models. Those adenosine-augmenting therapies are likewise able to improve cognitive function and to exert antipsychotic like activity. I am very excited by the perspective that reconstruction of adenosine homeostasis in the brain can affect epilepsy on several different beneficial levels.

What motivated you to become interested in this area of research?
Certainly a combination of conscious and unconscious decisions. When I was a child I almost died from a brain infection which leads to the development of epilepsy in 50% of cases (although at that time I didn’t even know what epilepsy is). Perhaps this spawned an early interest in the brain and how it works; today, I see how lucky I was that I was spared from any adverse effects from my childhood condition. One motivation for doing what I am doing: I want to give back to those that have not been spared from epilepsy.

When I did my undergraduate and graduate studies at Cologne University I started out with Biology and Biochemistry before moving into Neuroscience. Based on this broad education I like to explore general mechanisms, which are at the core of biology or biochemistry. This is one of the reasons why I am fascinated by adenosine, which was one of the first molecules at the origin of life.

What is your current research focus?
We currently have four major research foci:

  1. Development of new therapies to augment adenosine signaling in the brain in order to treat seizures and associated comorbidities in established epilepsy. Our goal is to move those therapies into the clinic and we hope to initiate first safety and feasibility trials in the near future.
  2. Development of strategies to prevent the development of epilepsy (i.e. prevention of epileptogenesis).
  3. Changes in a chemical modification of DNA (DNA methylation) affect the way that genes are expressed. We recently discovered that adenosine affects DNA methylation in the brain. A reduction in adenosine leads to an increase in DNA methylation, whereas an increase in DNA (e.g. induced by therapeutic intervention) leads to a reduction in DNA methylation. We try to understand how DNA methylation relates to epilepsy development and whether these processes can be controlled by adenosine therapy.
  4. We are interested in the mechanisms that regulate the birth of new neurons in the brain and how these processes relate to the development of epilepsy.

Can you share some of the latest findings?
Our most exciting finding is a therapeutic success in a rat animal model of progressive epilepsy development. Epilepsy in this model is characterized by adenosine deficiency, increased DNA methylation, increased sprouting of a certain type of neuron in the hippocampus, and progressive worsening of the epileptic condition. We have developed a silk-based brain implant to deliver a defined dose of adenosine to the brain over a limited period of time. Implantation of the adenosine-releasing silk reduced DNA methylation, prevented sprouting of the neurons and blocked the progression of epilepsy development long-term. This finding is important, (i) because it provides the first experimental evidence that increased DNA methylation is functionally implicated in epilepsy development, and (ii) because it offers a therapeutic strategy to prevent epileptogenesis, an exciting possibility that we currently continue to explore with the generous support by CURE.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Our ultimate goal is to be able to prevent the development of epilepsy in persons at risk and hopefully to reverse the pathogenetic processes that led to the development of epilepsy. In other words: we hope to find a true cure for epilepsy. We aim to better define the epigenetic mechanisms by which adenosine affects epileptogenesis and disease progression in epilepsy.

We propose (i) that epigenome modification is an integral component of epileptogenesis; (ii) that adenosine, regulated by astrocytes, affects long-lasting changes in DNA methylation, and (iii) that adenosine-based therapies can prevent the development of epilepsy via epigenetic changes. We predict that the transient delivery of adenosine to the brain can reverse and permanently alter pathogenetic changes of the epigenome and thereby set back the ‘epileptogenic clock’. We therefore propose that adenosine-based modifications of the epigenome will bring us one step closer to finding a cure for acquired epilepsies. The expected outcome of our work is the prevention of seizures in the absence of side effects via an epigenetic therapeutic intervention.

Understanding the underlying mechanism has direct implications for the development of novel adenosine augmenting therapies aimed at the prevention of epileptogenesis. The demonstration that adenosine is an epigenetic regulator in the brain, which can affect epileptogenesis and disease progression in epilepsy, has exciting implications both for our understanding of epilepsy, as well as for the development of therapies to prevent epileptogenesis. As we have demonstrated previously, the focal mode of adenosine augmentation is devoid of sedative side effects . Importantly, the long-lasting therapeutic benefits of a transient adenosine therapy represent a key advance in preventing the development of epilepsy without any long-term adverse effects. We hope to develop a novel antiepileptogenic strategy. If successful, data from our current work could rapidly be translated clinically making use of current adenosine augmentation strategies that are in development in our laboratory.

What accomplishment—personal or professional—are you most proud of?
I am proud of my fabulous research team. Without those dedicated individuals our research achievements would not be possible. Building a productive, collaborative, multidisciplinary, and multinational research team can be challenging at times, but is a very rewarding experience.